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J Neurointerv Surg ; 12(2): 221-226, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31401562


BACKGROUND: Genetic risk factors play an important role in the pathogenesis of familial intracranial aneurysms (FIAs); however, the molecular mechanisms remain largely unknown. OBJECTIVE: To investigate potential FIA-causing genetic variants by rare variant interrogation and a family-based genomics approach in a large family with an extensive multigenerational pedigree with FIAs. METHOD: Exome sequencing (ES) was performed in a dominant likely family with intracranial aneurysms (IAs). Variants were analyzed by an in-house developed pipeline and prioritized using various filtering strategies, including population frequency, variant type, and predicted variant pathogenicity. Sanger sequencing was also performed to evaluate the segregation of the variants with the phenotype. RESULTS: Based on the ES data obtained from five individuals from a family with 7/21 living members affected with IAs, a total of 14 variants were prioritized as candidate variants. Familial segregation analysis revealed that NFX1 c.2519T>C (p.Leu840Pro) segregated in accordance with Mendelian expectations with the phenotype within the family-that is, present in all IA-affected cases and absent from all unaffected members of the second generation. This missense variant is absent from public databases (1000genome, ExAC, gnomAD, ESP5400), and has damaging predictions by bioinformatics tools (Gerp ++ score = 5.88, CADD score = 16.43, MutationTaster score = 1, LRT score = 0). In addition, 840Leu in NFX1 is robustly conserved in mammals and maps in a region before the RING-type zinc finger domain. CONCLUSION: NFX1 c.2519T>C (p.Leu840Pro) may contribute to the pathogenetics of a subset of FIAs.

Front Neurol ; 10: 179, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30915016


Objective: To evaluate the feasibility and effectiveness of the pipeline embolization device (PED) for the treatment of pediatric giant vertebrobasilar dissecting aneurysms (VBDAs). Methods: We retrospectively reviewed our institutional clinical database and identified 2,706 patients who presented with a diagnosis of intracranial aneurysms from January 2016 to June 2018. Among this group, 153 patients were diagnosed with VBDAs, and 54 of these patients underwent PED therapy. The PED technique was used in four patients who were 18 years old or younger at the time of presentation (two males, two females; mean age 9.25 years; age range 8-11 years). Results: All four included pediatric patients were managed with the PED. One patient (25%) was treated with the PED alone, while three (75%) were treated with the PED and coils. One patient died from brainstem infarction or compression of the brainstem, while follow-up of the other three patients revealed favorable outcomes. The mass effect was reduced in cases 1, 2, and 3 on follow-up MRI performed 6 months after the PED procedure. Conclusions: PEDs could be feasible in the treatment of pediatric giant VBDAs. However, the safety and efficacy of this method have not been clarified in this special pediatric population, and long-term follow-up is still necessary.

J Hum Genet ; 63(11): 1119-1128, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30115950


Intracranial vertebral-basilar artery dissection (IVAD) is an arterial disorder leading to life-threatening consequences. Genetic factors are known to be causative to certain syndromic forms of IVAD. However, systematic study of the molecular basis of sporadic and isolated IVAD is lacking. To identify genetic variants contributing to the etiology of IVAD, we enrolled a cohort of 44 unrelated cases with a clinical diagnosis of isolated IVAD and performed whole-exome sequencing (WES) for all the participants; a trio exome sequencing approach was used when samples from both parents were available. Four previously reported disease-causing heterozygous variants (three in COL3A1 and one in FBN1) and seven novel heterozygous variants in IVAD-related genes were identified. In addition, six variants in novel IVAD genes including two de novo heterozygous nonsynonymous variants (each in VPS52 and CDK18), two stop-gain variants (each in MYH9 and LYL1), and two heterozygous biallelic variants in TNXB were considered to be possibly contributing to the phenotype, with unknown significance according to the existing knowledge. A significantly higher mutational rate of IVAD candidate genes was observed in patients versus our in-house controls (P = 0.002) (DISCO study, , n = 2248). Our study provided a mutational landscape for patients with isolated IVAD.

Aneurisma Dissecante/genética , Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Aneurisma Intracraniano/genética , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Estudos de Coortes , Colágeno Tipo III/genética , Feminino , Fibrilina-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Motores Moleculares/genética , Cadeias Pesadas de Miosina/genética , Proteínas de Neoplasias/genética
J Med Genet ; 55(10): 675-684, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30120215


BACKGROUND: Brain arteriovenous malformations (BAVM) represent a congenital anomaly of the cerebral vessels with a prevalence of 10-18/100 000. BAVM is the leading aetiology of intracranial haemorrhage in children. Our objective was to identify gene variants potentially contributing to disease and to better define the molecular aetiology underlying non-syndromic sporadic BAVM. METHODS: We performed whole-exome trio sequencing of 100 unrelated families with a clinically uniform BAVM phenotype. Pathogenic variants were then studied in vivo using a transgenic zebrafish model. RESULTS: We identified four pathogenic heterozygous variants in four patients, including one in the established BAVM-related gene, ENG, and three damaging variants in novel candidate genes: PITPNM3, SARS and LEMD3, which we then functionally validated in zebrafish. In addition, eight likely pathogenic heterozygous variants (TIMP3, SCUBE2, MAP4K4, CDH2, IL17RD, PREX2, ZFYVE16 and EGFR) were identified in eight patients, and 16 patients carried one or more variants of uncertain significance. Potential oligogenic inheritance (MAP4K4 with ENG, RASA1 with TIMP3 and SCUBE2 with ENG) was identified in three patients. Regulation of sma- and mad-related proteins (SMADs) (involved in bone morphogenic protein (BMP)/transforming growth factor beta (TGF-ß) signalling) and vascular endothelial growth factor (VEGF)/vascular endotheliual growth factor recepter 2 (VEGFR2) binding and activity (affecting the VEGF signalling pathway) were the most significantly affected biological process involved in the pathogenesis of BAVM. CONCLUSIONS: Our study highlights the specific role of BMP/TGF-ß and VEGF/VEGFR signalling in the aetiology of BAVM and the efficiency of intensive parallel sequencing in the challenging context of genetically heterogeneous paradigm.

Proteínas Morfogenéticas Ósseas/genética , Variação Genética , Malformações Arteriovenosas Intracranianas/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Fator de Crescimento Transformador beta/genética , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Animais Geneticamente Modificados , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , China , Estudos de Coortes , Modelos Animais de Doenças , Família , Feminino , Heterozigoto , Humanos , Malformações Arteriovenosas Intracranianas/diagnóstico por imagem , Malformações Arteriovenosas Intracranianas/patologia , Masculino , Transdução de Sinais , Sequenciamento Completo do Exoma , Peixe-Zebra